Shortages of key drugs endanger patients

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ByRob Stein

May 1, 2011

Doctors, hospitals and federal regulators are struggling to cope with an unprecedented surge in drug shortages in the United States that is endangering cancer patients, heart attack victims, accident survivors and a host of other ill people.

A record 211 medications became scarce in 2010 — triple the number in 2006 — and at least 89 new shortages have been recorded through the end of March, putting the nation on track for far more scarcities.

The paucities are forcing some medical centers to ration drugs — including one urgently needed by leukemia patients — postpone surgeries and other care, and scramble for substitutes, often resorting to alternatives that may be less effective, have more side effects and boost the risk for overdoses and other sometimes-fatal errors.

The causes vary from drug to drug, but experts cite a confluence of factors: Consolidation in the pharmaceutical industry has left only a few manufacturers for many older, less profitable products, meaning that when raw material runs short, equipment breaks down or government regulators crack down, the snags can quickly spiral into shortages.

“It seems like there were a lot of things happening with consolidations and quality issues and more things coming from overseas,” said Allen J. Vaida, executive director of the Institute for Safe Medicine Practices, a nonprofit group that helped organize a conference last fall to examine the issue. “It just reached a point where the number of shortages was slowly going up and up, and now we have a national crisis with this huge shortage of critical medications.”

No one is systematically tracking the toll of the shortages, but reports are emerging of delayed treatments, anxious searches for desperately needed drugs, devastating injuries from mistakes and less-adequate drugs, and even possible deaths.

Federal regulators have been rushing to alleviate the shortages, sometimes helping firms resume production more quickly or approving emergency imports of supplies from overseas.

The Food and Drug Administration eased a shortage of the anesthetic propofol last year by allowing foreign importation, for example, and this year approved bringing in several other medications, including two cancer drugs.

“The types of products we’re seeing shortages of are really concerning,” said Valerie Jensen, who heads the FDA’s Drug Shortages Program. “This is affecting oncology drugs, critical-care drugs, emergency medicine drugs. We’re doing everything we can under our current authority to try to deal with this situation.”

In Congress, legislation has been introduced to address the problem. For example, a bill would require companies to notify the FDA in advance about anything that might cause a shortage and give the agency new powers to try to assuage them.

“We can’t put patients’ lives at risk simply because there’s some snafus in a process or a manufacturer decides it’s less profitable to make a certain drug,” said Sen. Amy Klobuchar (D-Minn.). “Patients deserve better than that.”

‘Very global supply chain’

Many of the shortages involve older, cheaper generic medications that are less profitable, causing many firms to stop producing them and leaving fewer sources. Most involve “sterile injectable” medications that are more complicated to produce and therefore are more prone to manufacturing problems.

In addition, drug companies increasingly rely on raw materials from other countries.

“We’ve certainly reached a very global supply chain for drug products, with the active ingredients typically made outside of the United States,” said Gordon Johnston, vice president for regulatory sciences at the Generic Pharmaceutical Association. “It could be Europe, India — some cases China. If there’s a problem at a facility in Italy or India, it leads to disruption of the drug supply in the United States.”

Some industry representatives blame part of the problem on increased oversight by the FDA, which has made drug safety a higher priority after coming under intense criticism for being too lax.

“As you know right now, FDA has taken a heightened approach towards drug safety,” said Maya Bermingham, senior assistant general counsel at the Pharmaceutical Research and Manufacturers of America. “FDA has stepped up inspections. The more you look, the more you may discover problems.”

While acknowledging that the industry needs to do a better job of coordination, some company officials said the agency should coordinate enforcement actions and drug shortage issues more closely to avoid administrative requirements that cause interruptions.

“We’re not sure how much of that is going on recently because we’ve seen more and more shortages in the industry. We think that maybe some of those coordination issues can be worked on,” said Joshua Gordon, vice president and general manager of specialty pharmaceuticals at Hospira, the largest producer of specialty generic sterile injectables.

Shortages of pre-loaded epinephrine syringes and propofol, for example, occurred when suppliers dropped out just as the FDA was demanding additional documentation, he said.

“They are very focused on taking quick and and aggressive action,” Gordon said. “We applaud the agency’s role in assuring quality, but it can slow things down significantly.”

FDA officials dispute that greater government oversight is a major factor, saying manufacturing problems were the cause of most shortages.

“There has not been a significant increase in domestic enforcement actions (seizure or injunction) for this class of products in recent years,” Jensen wrote in an e-mail.

‘Too many . . . will die’

Whatever the causes, many of the affected drugs are mainstays of medical care, such as the potent painkiller morphine, norepinephrine, which is commonly used in emergency rooms, and electrolytes, which are often given to patients in intensive care.

But shortages have been reported in many categories of drugs, including antibiotics, and drugs central to the treatment of many cancers, forcing oncologists to delay or alter carefully timed chemotherapy regimens.

“We have heard some horror stories where patients are really begging to get the drugs from other sources and where practices or institutions are forced to kind of triage patients and save the drugs for those — quote — most curable, where they have the best prognosis and using substitutes where there isn’t a cure possibility,” Michael Link, president-elect of the American Society of Clinical Oncology.

The drug cytarabine has caused the most concern and gotten the most attention because it is highly effective for treating several forms of leukemia and lymphoma but must be administered as quickly as possible, especially to patients with acute myeloid leukemia.

“With this drug they can be cured and without this drug too many of them will certainly die. That’s the simplest way to put it,” said Deborah Banker, vice president for research communication at the Leukemia & Lymphoma Society. “The disease progresses so rapidly that untreated patients can sadly die within days. There is no time for delay and no certainty of a good outcome if you can’t get a full dose.”

Many hospitals are running low, and some have run out completely. That has required many facilities to ration the drug, giving priority to those who need it most urgently.

“It’s so unbelievable,” said Mary Collins, 57, of La Crosse, Wis., whose husband, Michael, 66, had problems obtaining cytarabine to fight lymphoma. “A cancer diagnosis is a long, very, very stressful circumstance. And then to learn that a particular drug is no longer available to you and that there seems to be no formalized mechanism in place to correct it just makes it worse.”

Cytarabine’s scarcity was caused by hitches that two out of the three manufacturers hit in obtaining raw materials, as well as the discovery of crystals in some shipments.

The third manufacturer was unable to make up for the shortfall. Some of the problems have been resolved, however, and the FDA is working on importing the drug.

The shortages are forcing hospital pharmacists to juggle supplies and hunt for new sources. Many hospitals, including several contacted in the Washington area, say they are usually able to patch together solutions.

But some resort to paying inflated prices or buying from unfamiliar suppliers, increasing the risk they may be getting counterfeits.

“When it becomes clear that some drug may be in short supply or going into a shortage, what happens is sometimes there are unsavory folks — small distributors — who buy up whatever is left and sell it back at exorbitant prices,” said Roslyne Shulman, director of policy development for the American Hospital Association.

‘Panic in the pharmacy’

When shortages occur, physicians turn to less optimal alternatives or find out too late that the drug they need is unavailable. Mark Warner, president of the American Society of Anesthesiologists, described two calamities that occurred in the past year because of shortages. In one, a 16-year-old boy suffered brain damage because doctors did not have one muscle relaxer needed to treat a complication from jaw surgery.

In another, a middle-aged woman was left in a permanent vegetative state because doctors did not have the drug epinephrine after she experienced complications from heart surgery.

“These are tragic cases,” Warner said. “It’s one of those things most anesthesiologists in the country think about when they are driving to work every day. We don’t know where the shortages are and they come on very quickly. ”

Nurses and doctors responding to emergencies, meanwhile, are losing precious minutes when they must work with unfamiliar substitutes or recalculate dosages, increasing the chances of overdosing or under-dosing patients. One of the biggest problems is a shortage of syringes pre-filled with precisely measured doses.

“Grabbing the right medication out of a crash cart that’s already in a syringe is a big advantage over having to get out the syringe, get out the needle, get the medication and get the measurement right,” said Angela Gardner, an emergency medicine physician at the University of Texas Southwestern Medical Center in Dallas and immediate past president of the American College of Emergency Physicians. “Those minutes are lives.”

Many hospitals are recalibrating electronic medication delivery systems or preparing the correct doses ahead of time, especially for the emergency room, to minimize mistakes.

“We’ve been extremely fortunate using strategies in cooperation with our medical staff,” said Jay Barbaccia, head pharmacist at the Washington Hospital Center. “We’ve had a lot of panic and inconvenience but minimal, if any, impact on our ability to provide care. It makes my life miserable — the panic is in the pharmacy when we’re scrambling around to find alternatives.”

At least two patients reportedly died from overdoses of hydromorphone they received because of a morphine shortage.

At least 19 patients were sickened and nine died in Alabama this year after being infused with a solution through their feeding tubes that was apparently contaminated with bacteria by a pharmacy using an unfamiliar ingredient because of a shortage.

The shortage occurred because the manufacturer had trouble getting the product’s packaging.

“It’s horrible. It’s something that shouldn’t have happened,” said Donald J. Mottern of Alabaster, Ala., whose 71-year-old mother was one of the victims. “We lost the matriarch of our family. The loss to our family has left each of us very hollow.”

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